Dry eye conditions afflict an ever-growing segment of society, are associated with increased ocular morbidity and result in considerable medical expense. The most common cause of dry eye conditions is insufficient aqueous tear production by the lacrimal glands. In several instances (e.g., Sjogren's syndrome), the underlying cause of lacrimal gland hypofunction is unknown, but is associated with the presence of focal lymphocytic infiltrates which are surrounded by substantial, otherwise normal appearing secretory epithelial (acinar) cells. This observation points to the poorly understood role of the immune system in the regulation of lacrimal gland physiology in general, and aqueous tear production in particular, as a necessary and potentially productive new area of research. The long-term objectives of this research plan are to further our understanding concerning the regulation of aqueous tear production by the lacrimal glands. Specifically, the regulation of ion transport processes will be investigated with regard to their role in the development and/or progression of lacrimal gland hypofunction. This proposal tests the hypothesis that the immune system contributes to the regulation of fluid secretion by the lacrimal glands by affecting the activity or expression of ion transporters. The specific aims of this research proposal are to: l. Investigate the rapid regulation of ion transport by neural and immune factors that are present in lacrimal gland tissue in normal and disease states. In addition, determine the specific second messenger systems that translate binding of regulatory agents into changes in ion transport, and ultimately fluid secretion, by lacrimal acinar cells. 2. Examine the activity and molecular expression of ion transporters in response to chronic exposure of cultured lacrimal acinar cells to immune agents. Since dry eye conditions affect women much more frequently than men, studies will be performed with tissue obtained from female animals. However, this investigation will go beyond any performed to date using either male or female-derived lacrimal tissue. Thus, while studies will be performed using tissue derived from females, information gathered will be relevant to the regulation of lacrimal fluid secretion of either gender. The primary methods used to achieve these objectives incorporate pH- and Ca2+- sensitive fluorescent probes, electron microscopy, and Northern analysis using freshly prepared, or primary cultures of, lacrimal gland acinar cells.